The proximal tubule (PT) of the kidney is the primary site for reabsorption of ions, solutes, and filtered low molecular weight (LMW) proteins. PT cells acutely modulate ion transport capacity in respond to changes in fluid shear stress (FSS) that accompany alterations in glomerular filtration rate. This proposal is focused on understanding whether PT cells also adjust the capacity of megalin-and cubilin- mediated endocytosis of LMW proteins in response to altered demand. Defective uptake of these proteins leads to tubular proteinuria, which can eventually lead to renal failure. We have discovered that apical endocytosis of the megalin/cubilin ligand albumin as well as fluid phase markers is markedly increased upon exposure of PT cells to FSS. Moreover, primary cilia are required for this response. The aims of this proposal are to (1) determine how changes in FSS are transduced into effects on apical endocytosis and (2) determine whether defective modulation of flow-dependent endocytosis contributes to LMW proteinuria observed in animal models for Lowe Syndrome, an X- linked disorder that may involve defects in ciliogenesis. We have assembled an outstanding team of investigators with essential expertise to carry out this broad range of studies. The results of our experiments will provide key information about a newly discovered pathway that plays an essential role in maintaining kidney function.